Impact of gastric emptying and small intestinal transit on blood glucose, intestinal hormones, glucose absorption in the morbidly obese.

OBJECTIVE: This study evaluated gastric emptying (GE) and small intestinal (SI) transit in people with morbid obesity and their relationships to glycaemia, incretin hormones, and glucose absorption METHODS: GE and caecal arrival time (CAT) of a mixed meal were assessed in 22 morbidly obese (50.2 ± 2.5 years; 13 F:9 M; BMI: 48.6 ± 1.8 kg/m2) and 10 lean (38.6 ± 8.4 years; 5 F:5 M; BMI: 23.9 ± 0.7 kg/m2) subjects, using scintigraphy. Blood glucose, plasma 3-O-methylglucose, insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were measured. Insulin sensitivity and resistance were also quantified RESULTS: When compared with lean subjects, GE (t50: 60.7 ± 6.5 vs. 41.1 ± 7.3 min; P = 0.04) and CAT (221.5 ± 9.8 vs. 148.0 ± 7.1 min; P = 0.001) of solids were prolonged in morbid obesity. Postprandial rises in GIP (P = 0.001), insulin (P = 0.02), glucose (P = 0.03) and 3-O-methylglucose (P = 0.001) were less. Whereas GLP-1 increased at 45 mins post-prandially in lean subjects, there was no increase in the obese (P = 0.04). Both fasting (P = 0.045) and postprandial (P = 0.012) plasma glucagon concentrations were higher in the obese CONCLUSIONS: GE and SI transit are slower in the morbidly obese, and associated with reductions in postprandial glucose absorption, and glycaemic excursions, as well as plasma GIP and GLP-1.

Relationships of the early insulin secretory response and oral disposition index with gastric emptying in subjects with normal glucose tolerance.

The oral disposition index, the product of the early insulin secretory response during an oral glucose tolerance test and insulin sensitivity, is used widely for both the prediction of, and evaluation of the response to interventions, in type 2 diabetes. Gastric emptying, which determines small intestinal exposure of nutrients, modulates postprandial glycemia. The aim of this study was to determine whether the insulin secretory response and the disposition index (DI) related to gastric emptying in subjects with normal glucose tolerance. Thirty-nine subjects consumed a 350 mL drink containing 75 g glucose labeled with 99mTc-sulfur colloid. Gastric emptying (by scintigraphy), blood glucose (G) and plasma insulin (I) were measured between t = 0-120 min. The rate of gastric emptying was derived from the time taken for 50% emptying (T50) and expressed as kcal/min. The early insulin secretory response was estimated by the ratio of the change in insulin (∆I0-30) to that of glucose at 30 min (∆G0-30) represented as ∆I0-30/∆G0-30 Insulin sensitivity was estimated as 1/fasting insulin and the DI was then calculated as ∆I0-30/∆G0-30 × 1/fasting insulin. There was a direct relationship between ∆G0-30 and gastric emptying (r = 0.47, P = 0.003). While there was no association of either ∆I0-30 (r = -0.16, P = 0.34) or fasting insulin (r = 0.21, P = 0.20), there were inverse relationships between the early insulin secretory response (r = -0.45, P = 0.004) and the DI (r = -0.33, P = 0.041), with gastric emptying. We conclude that gastric emptying is associated with both insulin secretion and the disposition index in subjects with normal glucose tolerance, such that when gastric emptying is relatively more rapid, both the early insulin secretory response and the disposition index are less. These findings should be interpreted as "hypothesis generating" and provide the rationale for longitudinal studies to examine the impact of baseline rate of gastric emptying on the prospective risk of type 2 diabetes.

Effects of Fat and Protein Preloads on Pouch Emptying, Intestinal Transit, Glycaemia, Gut Hormones, Glucose Absorption, Blood Pressure and Gastrointestinal Symptoms After Roux-en-Y Gastric Bypass.

BACKGROUND: The aim was to determine the effects of fat and protein preloads on pouch emptying (PE), caecal arrival time (CAT), glucose absorption, blood glucose (BSL), gut hormones, haemodynamics and gastrointestinal (GI) symptoms in subjects who had undergone Roux-en-Y gastric bypass (RYGB) >12 months previously. METHODS: Ten RYGB subjects were studied on three occasions, in randomised order, receiving 200-ml preloads of either water, fat (30 ml olive oil) or whey protein (55 g), 30 min before a mixed meal. PE, CAT, BSL, plasma 3-O-methyl-D-glucopyranose (3-OMG), insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and glucagon, blood pressure (BP), heart rate (HR) and GI symptoms were assessed over 270 min. RESULTS: Although fat and protein preloads did not alter PE of either solids or liquids, the CAT of solids, but not liquids, was longer than that after the water preload (fat 68 ± 5 min and protein 71 ± 6 min vs. water 46 ± 5 min; P = 0.02). BSL elevated promptly after the meal on all days (P < 0.001), but after protein, the magnitude and integrated increases in the first 75 min were less than fat and water preloads (area under the curve (AUC(0-75 min)), 18.7 ± 18.2 vs. 107.2 ± 30.4 and 76.1 ± 19.3 mmol/L/min; P < 0.05). Compared to water preload, the protein and fat preloads were associated with greater increases in plasma insulin, GLP-1 and glucagon concentrations, a reduction in BP, and greater increases in HR, fullness, bloating and nausea. Plasma 3-OMG levels were lower after the protein than after the water and fat preloads (P < 0.001). CONCLUSIONS: Given its effects to attenuate post-prandial glycaemia, reduce intestinal glucose absorption and potentiate the "incretin response", without inducing more adverse post-prandial GI symptom, protein preload may prove clinically useful in RYGB patients and warrant further evaluation, particularly in those with type 2 diabetes (T2DM) and/or dumping syndrome.

Relationships of Early And Late Glycemic Responses With Gastric Emptying During An Oral Glucose Tolerance Test.

CONTEXT: The early glycemic response during a 75-g oral glucose tolerance test (OGTT) is directly related to the rate of gastric emptying (GE). There is little information about the effect of GE on the blood glucose at either 60 min (a predictor of diabetes) or 120 min (used diagnostically). OBJECTIVE: This study aimed to evaluate the relationships between glycemic responses at 30, 60, and 120 min and GE following a 75-g OGTT in subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (T2D). DESIGN, SETTING, AND SUBJECTS: Eighty-two subjects in the general community without diabetes (57 NGT, 25 IGT) and 16 with T2D consumed a 75-g glucose drink labeled with (99m)Tc-sulfur colloid. GE (by scintigraphy) and glycemia were measured from t = 0-120 min and relationships between blood glucose (absolute, change from baseline, and area under the curve) and GE at 30, 60, and 120 min determined. RESULTS: There were no differences in GE. There were relationships between the blood glucose at 30 min and GE (NGT: r = 0.40; P < .01; IGT: r = 0.49; P = .02; T2D: r = 0.62; P = .01). There was also a relationship between the blood glucose at 60 min and GE in IGT (r = 0.52; P = .02) and T2D (r = 0.77; P < .01), but not NGT (r = 0.16; P = .24). In NGT, there was an inverse relationship between blood glucose at 120 min and GE (r = -0.30; P = .02), but not in IGT (r = 0.05; P = .82) or T2D (r = 0.37; P = .16). CONCLUSIONS: GE is a determinant of the glycemic response to an OGTT in NGT, IGT, and T2D but these relationships differ and are time dependent.

Accelerated intestinal glucose absorption in morbidly obese humans: relationship to glucose transporters, incretin hormones, and glycemia.

CONTEXT: Intestinal glucose absorption is mediated by sodium-dependent glucose transporter 1 (SGLT-1) and glucose transporter 2 (GLUT2), which are linked to sweet taste receptor (STR) signaling and incretin responses. OBJECTIVE: This study aimed to examine intestinal glucose absorption in morbidly obese humans and its relationship to the expression of STR and glucose transporters, glycemia, and incretin responses. DESIGN/SETTING/PARTICIPANTS: Seventeen nondiabetic, morbidly obese subjects (body mass index [BMI], 48 ± 4 kg/m(2)) and 11 lean controls (BMI, 25 ± 1 kg/m(2)) underwent endoscopic duodenal biopsies before and after a 30-minute intraduodenal glucose infusion (30 g glucose and 3 g 3-O-methylglucose [3-OMG]). MAIN OUTCOME MEASURES: Blood glucose and plasma concentrations of 3-OMG, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), insulin, and glucagon were measured over 270 minutes. Expression of duodenal SGLT-1, GLUT2, and STR (T1R2) was quantified by PCR. RESULTS: The increase in plasma 3-OMG (P < .001) and blood glucose (P < .0001) were greater in obese than lean subjects. Plasma 3-OMG correlated directly with blood glucose (r = 0.78, P < .01). In response to intraduodenal glucose, plasma GIP (P < .001), glucagon (P < .001), and insulin (P < .001) were higher, but GLP-1 (P < .001) was less in the obese compared with lean. Expression of SGLT-1 (P = .035), but not GLUT2 or T1R2, was higher in the obese, and related to peak plasma 3-OMG (r = 0.60, P = .01), GIP (r = 0.67, P = .003), and insulin (r = 0.58, P = .02). CONCLUSIONS: In morbid obesity, proximal intestine glucose absorption is accelerated and related to increased SGLT-1 expression, leading to an incretin-glucagon profile promoting hyperinsulinemia and hyperglycemia. These findings are consistent with the concept that accelerated glucose absorption in the proximal gut underlies the foregut theory of obesity and type 2 diabetes.

Effects of Posture and Meal Volume on Gastric Emptying, Intestinal Transit, Oral Glucose Tolerance, Blood Pressure and Gastrointestinal Symptoms After Roux-en-Y Gastric Bypass.

BACKGROUND: The purpose of this study is to determine the effects of posture and drink volume on gastric/pouch emptying (G/PE), intestinal transit, hormones, absorption, glycaemia, blood pressure and gastrointestinal (GI) symptoms after gastric bypass (Roux-en-Y gastric bypass (RYGB)). METHODS: Ten RYGB subjects were studied on four occasions in randomized order (sitting vs. supine posture; 50 vs. 150 ml of labelled water mixed with 3 g 3-O-methyl-D-glucose (3-OMG) and 50 g glucose). G/PE, caecal arrival time (CAT), blood glucose, plasma insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), peptide YY (PYY), 3-OMG, blood pressure, heart rate and GI symptoms were assessed over 240 min. Controls were ten volunteers with no medical condition or previous abdominal surgery, who were studied with the 150-ml drink in the sitting position. RESULTS: Compared to controls, PE (P < 0.001) and CAT (P < 0.001) were substantially more rapid in RYGB subjects. In RYGB, PE was more rapid in the sitting position (2.5 ± 0.7 vs. 16.6 ± 5.3 min, P = 0.02) and tends to be faster after 150 ml than the 50-ml drinks (9.5 ± 2.9 vs. 14.0 ± 3.5 min, P = 0.16). The sitting position and larger volume drinks were associated with greater releases of insulin, GLP-1 and PYY, as well as more hypotension (P < 0.01), tachycardia (P < 0.01) and postprandial symptoms (P < 0.001). CONCLUSIONS: Pouch emptying, blood pressure and GI symptoms after RYGB are dependent on both posture and meal volume.

Rapid gastric and intestinal transit is a major determinant of changes in blood glucose, intestinal hormones, glucose absorption and postprandial symptoms after gastric bypass.

OBJECTIVE: To evaluate the effect of modulating pouch emptying (PE) and SI transit of glucose after Roux-en-Y gastric bypass (RYGB) on blood glucose, incretin hormones, glucose absorption and gastrointestinal (GI) symptoms. METHODS: Ten RYGB patients were studied twice in random order, receiving either a 150 ml glucose drink (200 kcal) or the same solution infused into the proximal Roux-limb at 4 kcal/min. Data were compared with 10 healthy volunteers who received a 4 kcal/min duodenal infusion. PE, cecal arrival time (CAT), blood glucose, plasma 3-O-methylglucose (3-OMG), insulin, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1), and GI symptoms were measured. RESULTS: In RYGB subjects, the glucose drink emptied very rapidly (PE t50 = 3 ± 1 min) and intestinal glucose infusion was associated with higher blood glucose and plasma 3-OMG, but lower plasma GLP-1, GIP, insulin, and GI symptoms than oral glucose (all P < 0.001), and comparable to volunteers. In RYGB subjects, CAT correlated inversely with peak GLP-1 (r = -0.73, P = 0.01), and plasma 3-OMG correlated tightly blood glucose (r = 0.94, P < 0.0001). CONCLUSIONS: After RYGB, reducing intestinal glucose delivery to 4 kcal/min is associated with higher blood glucose, greater glucose absorption, lower incretin responses, and less GI symptoms, supporting rapid transit contribution to the exaggerated incretin responses and "dumping symptoms".

Small intestinal glucose exposure determines the magnitude of the incretin effect in health and type 2 diabetes.

The potential influence of gastric emptying on the "incretin effect," mediated by glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), is unknown. The objectives of this study were to determine the effects of intraduodenal (ID) glucose infusions at 2 (ID2) and 4 (ID4) kcal/min (equating to two rates of gastric emptying within the physiological range) on the size of the incretin effect, gastrointestinal glucose disposal (GIGD), plasma GIP, GLP-1, and glucagon secretion in health and type 2 diabetes. We studied 10 male BMI-matched controls and 11 male type 2 patients managed by diet or metformin only. In both groups, GIP, GLP-1, and the magnitude of incretin effect were greater with ID4 than ID2, as was GIGD; plasma glucagon was suppressed by ID2, but not ID4. There was no difference in the incretin effect between the two groups. Based on these data, we conclude that the rate of small intestinal glucose exposure (i.e., glucose load) is a major determinant of the comparative secretion of GIP and GLP-1, as well as the magnitude of the incretin effect and GIGD in health and type 2 diabetes.

Acute effects of oral preloads with increasing energy density on gastric emptying, gut hormone release, thermogenesis and energy intake, in overweight and obese men.

This study investigated the effect of high- and low-energy density preloads on gastrointestinal and metabolic factors, which act to regulate acute energy intake. Sixteen overweight and obese men (BMI range: 27.2-36.5 kg/m2) each received 3 oral preloads in randomised order: i) high-energy-density, high-fat (1.5 kcal/g), ii) low-energy density, high-fat (1.1 kcal/g), and iii) low-energy-density, high-protein (1.1 kcal/g). Over 180 min, gastric emptying, plasma glucagon-like peptide-1 concentrations, and diet-induced thermogenesis were assessed, and subsequent energy intake was determined. Total energy intake did not differ between preloads (high-energy-density, high-fat, 2059±72 kilocalories (kcal); low-energy-density, high-fat, 1876±91 kcal; and low-energy-density, high protein, 1867±63 kcal). Gastric emptying was slower following the high-energy-density, high-fat preload (158±8 min) compared with the low-energy-density, high-protein preload (130±9 min) (p=0.05), but did not differ between the high-energy-density, high-fat and low-energy-density, high-fat (147±8 min) preloads. Plasma glucagon- like peptide-1 did not differ substantially between preloads. Diet-induced thermogenesis was lower following high-energy-density, high-fat (10.4±0.7 %) than low-energy-density, high-fat (14.9±1.2 %) and low-energy density, high-protein (18.1±1.1 %) preloads (p<0.01 for both). We conclude that an increased energy density slows gastric emptying and reduces thermogenesis, but that a high fat content overrides the effect of energy density on gastric emptying. The counter-regulatory modulation of these gastric and metabolic factors may explain, at least in part, the lack of differences in subsequent energy intake in response to oral preloads with increasing energy density.

Staff responses to behaviour that challenges: the role of knowledge, attributions, and emotion regulation style.

BACKGROUND: In this study, we explored the extent to which the knowledge and attributions of support staff predicted their reported helping behaviour in relation to people with an intellectual disability who displayed challenging behaviour (CB), and whether emotion regulation style moderated the relationship between attributions and this helping behaviour. METHOD: Participants (N = 107) completed self-report measures of knowledge of the meaning and management of CB, causal attributions and behavioural response to CB, and emotion regulation style. RESULTS: Knowledge and helpful attributions were significantly correlated with reported helping behaviour; however, in a regression analysis with both predictors, only knowledge significantly contributed to the variance. No moderating effect was found for emotion regulation styles on the relationship between attributions and reported helping behaviour. CONCLUSION: Knowledge was the only significant predictor of reported positive staff approaches in managing CB, giving some support for the provision of staff training aimed at increasing knowledge, rather than changing attributions.

Gastric emptying, mouth-to-cecum transit, and glycemic, insulin, incretin, and energy intake responses to a mixed-nutrient liquid in lean, overweight, and obese males.

Observations relating to the impact of obesity on gastric emptying (GE) and the secretion of gut hormones are inconsistent, probably because of a lack of studies in which GE, gastrointestinal hormone release, and energy intake (EI) have been evaluated concurrently with previous patterns of nutrient intake. GE is known to be a major determinant of postprandial glycemia and incretin secretion in health and type 2 diabetes. The aims of this study were to determine the effects of a mixed-nutrient drink on GE, oro-cecal transit, blood glucose, insulin and incretin concentrations and EI, and the relationship between the glycemic response to the drink with GE in lean, overweight, and obese subjects. Twenty lean, 20 overweight, and 20 obese males had measurements of GE, oro-cecal transit, and blood glucose, insulin, GLP-1, and GIP concentrations for 5 h after ingestion of a mixed-nutrient drink (500 ml, 532 kcal); EI at a subsequent buffet lunch was determined. Habitual EI was also quantified. Glycemic and insulinemic responses to the drink were greater in the obese (both P < 0.05) when compared with both lean and overweight, with no significant differences in GE, intragastric distribution, oro-cecal transit, incretins, or EI (buffet lunch or habitual) between groups. The magnitude of the rise in blood glucose after the drink was greater when GE was relatively more rapid (r = -0.55, P < 0.05). In conclusion, in the absence of differences in habitual EI, both GE and incretin hormones are unaffected in the obese despite greater glucose and insulin responses, and GE is a determinant of postprandial glycemia.

Intraduodenal protein modulates antropyloroduodenal motility, hormone release, glycemia, appetite, and energy intake in lean men.

BACKGROUND: Intraduodenal fat and carbohydrate modulate antropyloroduodenal motility and hormone release and suppress appetite and energy intake in a load-dependent manner. Protein also suppresses energy intake, but its effects on these gastrointestinal factors and their role in the appetite-suppressive effects of protein remain unclear. OBJECTIVE: We aimed to characterize the effects of different intraduodenal protein loads on antropyloroduodenal pressures, gastrointestinal hormone release, glucose and insulin concentrations, appetite perceptions, and energy intake. DESIGN: Sixteen lean, healthy men were studied on 4 occasions in a randomized, double-blind fashion. Antropyloroduodenal pressures, plasma glucagon-like peptide 1 (GLP-1), cholecystokinin, peptide YY, ghrelin, blood glucose, serum insulin, and appetite were measured during 60-min, 4-mL/min intraduodenal infusions of protein at 0.5, 1.5, or 3 kcal/min or saline (control). Energy intakes at a buffet lunch consumed immediately after the infusion were quantified. RESULTS: Increases in the load of protein resulted in greater suppression of antral motility, greater stimulation of basal and isolated pyloric pressures and plasma cholecystokinin and GLP-1 concentrations, and greater suppression of energy intake. However, energy intake was reduced only after a protein load of 3 kcal/min compared with after all other treatments (P < 0.05). The suppression of energy intake after adjustment for cholecystokinin, GLP-1, and insulin was related inversely with basal pyloric pressure (r = -0.51, P < 0.001). CONCLUSION: The acute effects of intraduodenal protein on antropyloroduodenal motility, gastrointestinal hormone release, glucose, and insulin are load dependent and contribute to the suppression of energy intake. This trial was registered at www.anzctr.org.au as 12610000376044.

Effects of fat, protein, and carbohydrate and protein load on appetite, plasma cholecystokinin, peptide YY, and ghrelin, and energy intake in lean and obese men.

While protein is regarded as the most satiating macronutrient, many studies have employed test meals that had very high and unsustainable protein contents. Furthermore, the comparative responses between lean and obese subjects and the relationships between energy intake suppression and gut hormone release remain unclear. We evaluated the acute effects of meals with modest variations in 1) fat, protein, and carbohydrate content and 2) protein load on gastrointestinal hormones, appetite, and subsequent energy intake in lean and obese subjects. Sixteen lean and sixteen obese men were studied on four occasions. Following a standardized breakfast, they received for lunch: 1) high-fat (HF), 2) high-protein (HP), 3) high-carbohydrate/low-protein (HC/LP), or 4) adequate-protein (AP) isocaloric test meals. Hunger, fullness, and gut hormones were measured throughout, and at t = 180 min energy intake at a buffet meal was quantified. In lean subjects, hunger was less and fullness greater following HF, HP, and AP compared with HC/LP meals, and energy intake was less following HF and HP compared with HC meals (P < 0.05). In the obese subjects, hunger was less following HP compared with HF, HC/LP, and AP meals, and energy intake was less following HP and AP compared with HF and HC meals (P < 0.05). There were no major differences in hormone responses to the meals among subject groups, but the CCK and ghrelin responses to HP and AP were sustained in both groups. In conclusion, HP meals suppress energy intake in lean and obese subjects, an effect potentially mediated by CCK and ghrelin, while obese individuals appear to be less sensitive to the satiating effects of fat.

Comparative effects of variations in duodenal glucose load on glycemic, insulinemic, and incretin responses in healthy young and older subjects.

CONTEXT: Aging is associated with deteriorating glucose tolerance. Studies assessing glucose tolerance and subsequent insulin and incretin hormone release often fail to take into account the rate of gastric emptying when evaluating these responses. OBJECTIVE: Our objective was to determine the comparative effects of variations in the small intestinal glucose load on the glycemic, insulinemic, and incretin responses in healthy young and older subjects. MATERIALS AND METHODS: Twelve healthy young (six males, six females; age 22.2±2.3 yr) and 12 older (six males, six females; age 68.7±1.0 yr) subjects had measurements of blood glucose, serum insulin and plasma incretin hormones [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] and calculations of insulin resistance (homeostatic model assessment) and ß-cell function corrected for insulin sensitivity, before and during intraduodenal infusions of glucose at 1, 2, or 3 kcal/min or saline for 60 minutes. The study was double-blinded and randomized, and performed in the Discipline of Medicine at the Royal Adelaide Hospital. RESULTS: At baseline, blood glucose and serum insulin were slightly higher in the older subjects (P<0.001), whereas GLP-1 and GIP were comparable between groups. In both groups, the glycemic, insulinemic, and GLP-1 responses were dependent on the duodenal glucose load in a nonlinear fashion (P<0.001). The glycemic response was greater (P<0.001) in the older subjects, whereas GLP-1 and GIP responses were comparable between groups. The older subjects were more insulin resistant (P<0.001) and had impaired ß-cell function, particularly at higher glucose loads (P<0.05). CONCLUSION: When glucose is infused into the small intestine at equal rates in healthy young and older subjects, GLP-1 and GIP responses are comparable, indicating that impaired incretin secretion does not account for age-related glucose intolerance.

The alpha (α)-glucosidase inhibitor, acarbose, attenuates the blood pressure and splanchnic blood flow responses to intraduodenal sucrose in older adults.

BACKGROUND: Postprandial hypotension is an important problem in the elderly and may be triggered by the increase in splanchnic blood flow induced by a meal. Acarbose attenuates the fall in blood pressure (BP) induced by oral sucrose and may be useful in the management of postprandial hypotension. It is not known whether the effect of acarbose on postprandial BP reflects slowing of gastric emptying and/or carbohydrate absorption nor whether acarbose affects splanchnic blood flow. We examined the effects of intraduodenal (ID) acarbose on the BP, heart rate, superior mesenteric artery (SMA) flow, and glycemic and insulin responses to ID sucrose in older participants--this approach excluded any "gastric" effect of acarbose. METHODS: Eight healthy participants (four male and four female, age 66-77 years) received an ID infusion of sucrose (~6 kcal/min), with or without acarbose (100 mg), over 60 minutes. BP, heart rate, SMA flow, blood glucose, and serum insulin were measured. RESULTS: Acarbose markedly attenuated the falls in systolic (p < .01) and diastolic (p < .05) BP and rises in heart rate (p < .05), SMA flow (p < .05), blood glucose (p < .01), and serum insulin (p < .05). The maximum fall in systolic BP and peak SMA flow was inversely related on the control day (r(2) = -.53, p < .05) but not with acarbose (r(2) = .03, p = .70). CONCLUSIONS: We conclude that in healthy older participants receiving ID sucrose, (a) acarbose markedly attenuates the hypotensive response by slowing carbohydrate absorption and attenuating the rise in splanchnic blood flow and (b) the fall in BP is related to the concomitant increase in SMA flow.

The oligosaccharide α-cyclodextrin has modest effects to slow gastric emptying and modify the glycaemic response to sucrose in healthy older adults.

In healthy older subjects, the glycaemic response to carbohydrate-containing meals is dependent on gastric emptying and intestinal absorption; when the latter is slowed, the magnitude of the rise in glucose is attenuated. The oligosaccharide α-cyclodextrin has been reported to diminish the glycaemic response to starch in young adults; this effect has been attributed to the inhibition of pancreatic amylase. We examined the effects of α-cyclodextrin on gastric emptying of, and the glycaemic and insulinaemic responses to, oral sucrose in healthy older subjects; as sucrose is hydrolysed by intestinal disaccharides, any effect(s) of α-cyclodextrin would not be attributable to amylase inhibition. A total of ten subjects (seven males and three females, age 68-76 years) were studied on 2 d. Gastric emptying, blood glucose and serum insulin were measured after ingestion of a 300 ml drink containing 100 g sucrose, labelled with (99m)Tc-sulphur colloid, with or without 10 g α-cyclodextrin. Gastric emptying was slowed slightly by α-cyclodextrin; this effect was evident between 135 and 195 min and was associated with a slight increase (P < 0·05) in distal stomach retention. After α-cyclodextrin, blood glucose was slightly less (P < 0·05) at 60 min, and serum insulin was less (P < 0·0005) at 90 and 120 min. There was no difference in the incremental areas under the curve (iAUC) for blood glucose, but there was a trend for the iAUC for serum insulin to be lower (P = 0·09) after α-cyclodextrin. We conclude that in a dose of 10 g, α-cyclodextrin has modest effects to slow gastric emptying of, and modify the glycaemic and insulinaemic responses to, oral sucrose, probably due to delayed intestinal carbohydrate absorption.

Effects of small intestinal glucose load on blood pressure, splanchnic blood flow, glycemia, and GLP-1 release in healthy older subjects.

Postprandial hypotension is an important problem, particularly in the elderly. The fall in blood pressure is dependent on small intestinal glucose delivery and, possibly, changes in splanchnic blood flow, the release of glucagon-like peptide-1 (GLP-1), and sympathetic nerve activity. We aimed to determine in healthy older subjects, the effects of variations in small intestinal glucose load on blood pressure, superior mesenteric artery flow, GLP-1, and noradrenaline. Twelve subjects (6 male, 6 female; ages 65-76 yr) were studied on four separate occasions, in double-blind, randomized order. On each day, subjects were intubated via an anesthetized nostril, with a nasoduodenal catheter, and received an intraduodenal infusion of either saline (0.9%) or glucose at a rate of 1, 2, or 3 kcal/min (G1, G2, G3, respectively), for 60 min (t = 0-60 min). Between t = 0 and 60 min, there were falls in systolic and diastolic blood pressure following G2 and G3 (P = 0.003 and P < 0.001, respectively), but no change during saline or G1. Superior mesenteric artery flow increased slightly during G1 (P = 0.01) and substantially during G2 (P < 0.001) and G3 (P < 0.001), but not during saline. The GLP-1 response to G3 was much greater (P < 0.001) than to G2 and G1. Noradrenaline increased (P < 0.05) only during G3. In conclusion, in healthy older subjects the duodenal glucose load needs to be > 1 kcal/min to elicit a significant fall in blood pressure, while the response may be maximal when the rate is 2 kcal/min. These observations have implications for the therapeutic strategies to manage postprandial hypotension by modulating gastric emptying.

Gastric emptying, incretin hormone secretion, and postprandial glycemia in cystic fibrosis--effects of pancreatic enzyme supplementation.

CONTEXT: Postprandial hyperglycemia is an important clinical problem in cystic fibrosis (CF), but the contribution of fat malabsorption, rapid gastric emptying, and the incretin axis has not been widely considered. OBJECTIVE: The aim of this study was to evaluate these aspects of gut function in nondiabetic CF patients. DESIGN AND SETTING: We conducted a randomized, double-blind, placebo-controlled crossover study at a clinical research laboratory. PATIENTS: Five nondiabetic CF patients (three males; age, 25.8 ± 1.0 yr; body mass index, 20.2 ± 1.1 kg/m(2)) with exocrine pancreatic insufficiency and six healthy subjects of similar age and body mass index participated in the study. INTERVENTIONS: CF patients consumed a radiolabeled mashed potato meal on 2 separate days, together with four capsules of Creon Forte (100,000 IU lipase) or placebo. Healthy subjects consumed the meal once, without pancreatic enzymes. MAIN OUTCOME MEASURES: Gastric emptying was measured using scintigraphy, and blood was sampled frequently for blood glucose and plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon concentrations. RESULTS: CF patients had more rapid gastric emptying (P < 0.001), impaired secretion of GLP-1 (P < 0.01) and GIP (P < 0.001), and greater postprandial glycemic excursions (P < 0.001) than healthy subjects. Pancreatic enzyme supplementation normalized gastric emptying and GLP-1 secretion and tended to increase glucagon (P = 0.08), but did not completely restore GIP secretion or normalize postprandial blood glucose. There was an excellent correlation between gastric emptying and blood glucose concentration at 60 min (R = 0.75; P = 0.01). CONCLUSIONS: Pancreatic enzyme supplementation plays an important role in incretin secretion, gastric emptying, and postprandial hyperglycemia in CF.

Exogenous glucagon-like peptide-1 attenuates the glycaemic response to postpyloric nutrient infusion in critically ill patients with type-2 diabetes.

INTRODUCTION: Glucagon-like peptide-1 (GLP-1) attenuates the glycaemic response to small intestinal nutrient infusion in stress-induced hyperglycaemia and reduces fasting glucose concentrations in critically ill patients with type-2 diabetes. The objective of this study was to evaluate the effects of acute administration of GLP-1 on the glycaemic response to small intestinal nutrient infusion in critically ill patients with pre-existing type-2 diabetes. METHODS: Eleven critically ill mechanically-ventilated patients with known type-2 diabetes received intravenous infusions of GLP-1 (1.2 pmol/kg/minute) and placebo from t = 0 to 270 minutes on separate days in randomised double-blind fashion. Between t = 30 to 270 minutes a liquid nutrient was infused intraduodenally at a rate of 1 kcal/min via a naso-enteric catheter. Blood glucose, serum insulin and C-peptide, and plasma glucagon were measured. Data are mean ± SEM. RESULTS: GLP-1 attenuated the overall glycaemic response to nutrient (blood glucose AUC30-270 min: GLP-1 2,244 ± 184 vs. placebo 2,679 ± 233 mmol/l/minute; P = 0.02). Blood glucose was maintained at < 10 mmol/l in 6/11 patients when receiving GLP-1 and 4/11 with placebo. GLP-1 increased serum insulin at 270 minutes (GLP-1: 23.4 ± 6.7 vs. placebo: 16.4 ± 5.5 mU/l; P < 0.05), but had no effect on the change in plasma glucagon. CONCLUSIONS: Exogenous GLP-1 in a dose of 1.2 pmol/kg/minute attenuates the glycaemic response to small intestinal nutrient in critically ill patients with type-2 diabetes. Given the modest magnitude of the reduction in glycaemia the effects of GLP-1 at higher doses and/or when administered in combination with insulin, warrant evaluation in this group. TRIAL REGISTRATION: ANZCTR:ACTRN12610000185066.

Effects of metoclopramide on duodenal motility and flow events, glucose absorption, and incretin hormone release in response to intraduodenal glucose infusion.

The contribution of small intestinal motor activity to nutrient absorption is poorly defined. A reduction in duodenal flow events after hyoscine butylbromide, despite no change in pressure waves, was associated with reduced secretion of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and a delay in glucose absorption. The aim of this study was to investigate the effect of metoclopramide on duodenal motility and flow events, incretin hormone secretion, and glucose absorption. Eight healthy volunteers (7 males and 1 female; age 29.8 ± 4.6 yr; body mass index 24.5 ± 0.9 kg/m²) were studied two times in randomized order. A combined manometry and impedance catheter was used to measure pressure waves and flow events in the same region of the duodenum simultaneously. Metoclopramide (10 mg) or control was administered intravenously as a bolus, followed by an intraduodenal glucose infusion for 60 min (3 kcal/min) incorporating the ¹4C-labeled glucose analog 3-O-methylglucose (3-OMG). We found that metoclopramide was associated with more duodenal pressure waves and propagated pressure sequences than control (P < 0.05 for both) during intraduodenal glucose infusion. However, the number of duodenal flow events, blood glucose concentration, and plasma 3-[¹4C]OMG activity did not differ between the two study days. Metoclopramide was associated with increased plasma concentrations of GLP-1 (P < 0.05) and GIP (P = 0.07) but lower plasma insulin concentrations (P < 0.05). We concluded that metoclopramide was associated with increased frequency of duodenal pressure waves but no change in duodenal flow events and glucose absorption. Furthermore, GLP-1 and GIP release increased with metoclopramide, but insulin release paradoxically decreased.